Melanoma differentiation associated gene-7/
interleukin-24 (mda-7/IL-24) encodes a tumor suppressor gene implicated in the growth of various
tumor types including
breast cancer. We previously demonstrated that recombinant adenovirus-mediated mda-7/IL-24 expression in the mammary glands of
carcinogen-treated (
methylnitrosourea, MNU) rats suppressed mammary
tumor development. Since most MNU-induced
tumors in rats contain activating mutations in Ha-ras, which arenot frequently detected in humans, we presently examined the effect of MDA-7/IL-24 on Her2/Neu-induced mammary
tumors, in which the RAS pathway is induced. We generated tet-inducible MDA-7/IL-24 transgenic mice and crossed them with Her2/Neu transgenic mice. Triple compound transgenic mice treated with
doxycycline exhibited a strong inhibition of
tumor development, demonstrating
tumor suppressor activity by MDA-7/IL-24 in immune-competent mice. MDA-7/IL-24 induction also inhibited growth of
tumors generated following injection of Her2/Neu
tumor cells isolated from triple compound transgenic mice that had not been treated with
doxycycline, into the mammary fat pads of isogenic FVB mice. Despite initial growth suppression,
tumors in triple compound transgenic mice lost mda-7/IL-24 expression and grew, albeit after longer latency, indicating that continuous presence of this
cytokine within tumor microenvironment is crucial to sustain
tumor inhibitory activity. Mechanistically, MDA-7/IL-24 exerted its
tumor suppression effect on HER2+
breast cancer cells, at least in part, through PERP, a member of PMP-22 family with growth arrest and apoptosis-inducing capacity. Overall, our results establish mda-7/IL-24 as a suppressor of mammary
tumor development and provide a rationale for using this
cytokine in the prevention/treatment of human
breast cancer.